Significant Overall Survival Benefit Research Articles

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

LBA3 Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage II–IIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IB–IIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage II–IIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage II–IIIA. Key secondary endpoints: DFS in stage IB–IIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n=339, placebo n=343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage II–IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p=0.0004; 100/470 events, 21% maturity); 5-year OS rate was 85% with osimertinib vs 73% with placebo. Median follow-up for OS in stage II–IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p<0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106 .

Stage III deficient mismatch repair colon patients get greater benefit from earlier starting oxaliplatin-based chemotherapy regimen

We evaluate the prognostic value of chemotherapy and other prognostic factors on overall survival among colon patients with deficient mismatch repair (dMMR), and determine the optimum time to start chemotherapy after surgery. Data of 306 colon cancer patients with dMMR who received radical surgery were collected from three Chinese centers between August 2012 and January 2018. Overall survival (OS) was assessed with the Kaplan–Meier method and log-rank. Cox regression analysis were used to assess influencing prognosis factors. The median follow-up time for all patients was 45.0 months (range, 1.0–100). There was a nonsignificant OS benefit from chemotherapy for patients with stage I and stage II disease, including high-risk stage II disease (log-rank p: 0.386, 0.779, 0.921), and a significant OS benefit for patients with stage III and stage IV disease for receiving post-operation chemotherapy (log-rank p = 0.002, 0.019). Stage III patients benefitted from chemotherapy regimens that contained oxaliplatin (log-rank p = 0.004), and Starting chemotherapy with oxaliplatin treatment earlier resulted in better outcomes (95% CI 0.013–0.857; p = 0.035). Chemotherapy regimens containing oxaliplatin can prolong the survival time of stage III and IV dMMR colon cancer patients. This beneficial manifestation was more pronounced after starting chemotherapy treatment early post operation. High risk stage II dMMR colon patients including T4N0M0 cannot benefit from chemotherapy.

Randomized phase 2 study of gemcitabine with or without ATR inhibitor berzosertib in platinum-resistant ovarian cancer: Final overall survival (OS) and biomarker analyses.

5512 Background: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (HR = 0.57, one-sided log-rank p = 0.044, which met the one-sided significance level of 0.1 used for sample size calculation). Final overall survival (OS) and corresponding biomarker analyses are reported here. Methods: Patients (pts) with platinum-resistant high-grade serous ovarian cancer and unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting, were randomized 1:1 to gemcitabine/berzosertib versus gemcitabine alone. Randomization was stratified based on platinum free interval (PFI), PFI≤3 months versus > 3 months. Crossover from gemcitabine to gemcitabine/berzosertib was allowed upon disease progression by RECIST 1.1. OS was a secondary endpoint while preplanned exploratory correlative studies included assessment of DNA repair pathways and replication stress (RS) alterations by targeted gene sequencing and/or immunohistochemistry (IHC). Results: Seventy pts were randomly assigned to treatment with gemcitabine/berzosertib (34 pts) or gemcitabine alone (36 pts); 15 pts crossed over from gemcitabine to gemcitabine/berzosertib. At the final OS analysis (92.9% maturity), median follow-up was 53.2 weeks in the gemcitabine/berzosertib and 43 weeks in the gemcitabine alone groups. Median OS in the intent-to-treat (ITT) population was 59.4 weeks in the gemcitabine/berzosertib group versus 43.0 weeks in the gemcitabine alone group (HR 0.79, 90% CI 0.52-1.2, one-sided p = 0.18). However, when patients who crossed over to gemcitabine/berzosertib were excluded from analysis, a significant OS benefit was observed with gemcitabine/berzosertib (HR 0.60, 90%CI 0.37−0.97); HR was 0.26 (90% CI 0.1−0.7) in pts with PFI≤3 months and 0.89 (90%CI 0.50−1.59) in pts with PFI > 3 months. Furthermore, significant OS benefit was observed in pts with RS-low tumors (HR 0.39, 90%CI 0.17−0.91, defined as tumors harboring no genomic RS alterations related to loss of RB pathway regulation and/or oncogene-induced RS) but not in pts with RS-high tumors (HR 0.74, 90%CI 0.35−1.56). Additional targeted gene sequencing and IHC analyses as well as analyses adjusting for patient crossover will be reported at the meeting. Conclusions: In the ITT population, gemcitabine/berzosertib did not significantly improve OS versus gemcitabine alone. Pts with PFI≤3 months and pts with RS-low tumors may derive a survival advantage from addition of berzosertib to gemcitabine in the platinum-resistant setting. Clinical trial information: NCT02595892 .

Prophylactic cranial irradiation in small cell lung cancer patients in the era of magnetic resonance imaging: A systematic review and meta-analysis.

e20636 Background: Patients with small cell lung cancer (SCLC) are at a particularly high risk for the development of brain metastases. Current guidelines recommend prophylactic cranial irradiation (PCI) for these patients to prevent brain metastases and prolong overall survival (OS), although the clinical evidence for recommendations stems from an era without routine use of brain imaging. We performed a systematic review and meta-analysis of all available studies reporting on PCI for SCLC patients with minimal inclusion restrictions to assesses the efficacy of PCI in patients with limited disease (LD) and extensive disease (ED) SCLC and focus on the impact of routine brain imaging. Methods: A literature search for studies reporting on PCI in SCLC patients performed in EMBASE, MEDLINE, CENTRAL, and grey literature sources identified 4,783 studies. Random-effects meta-analyses pooled hazard ratios (HR) for overall survival (OS) between PCI and no intervention groups. Results: 208 individual studies reported on outcomes related to PCI with 175 studies assessing survival differences associated with PCI, and 87 of these being amenable to meta-analysis. The majority (n = 79) were retrospective cohort studies. PCI was associated with improved OS in all SCLC patients (HR 0.60; 95% CI 0.55-0.65; n = 87 studies; n = 50,339 patients; I2= 77%), as well as in cohorts exclusively consisting of LD patients (HR 0.60; 95% CI 0.54-0.66; n = 58 studies; n = 22,417 patients; I2= 76%) or ED patients (HR 0.63; 95% CI 0.53-0.75; n = 23 studies; n = 24,997; I2= 75%). Only eight studies confirmed absence of IMD at restaging using magnetic resonance imaging in all patients and found OS no longer to be in favour of PCI (HR 0.75; 95% CI 0.50-1.12; n = 1,318 patients; I2= 77%). Pooled OS from randomized controlled trials was not associated with PCI (HR 0.88; 95% CI 0.65-1.12; n = 5 studies; n = 925 patients; I2= 62.5%). Among studies not amenable to meta-analysis for OS, 4 radiographically confirmed absence of IMD, but none found OS to be in favour of PCI. Conclusions: Administration of PCI is associated with a significant OS benefit, but not when considering studies that radiographically confirmed absence of IMD at restaging or randomized controlled trials, suggesting that patient selection may be contributing to this observation.

Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC).

4502 Background: In the phase 3 CLEAR trial, L+P showed clinically meaningful and statistically significant benefits in PFS (primary endpoint) and OS, and improved ORR compared with S in 1L aRCC (Motzer NEJM 2021). Here, we report 4-yr follow-up results from the final prespecified OS analysis of CLEAR (data cutoff: 31 Jul 2022). Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomized (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were geographic region and MSKCC prognostic risk group. This final prespecified OS analysis was triggered by ~304 death events in 2 arms. OS, PFS, ORR, duration of response (DOR), and PFS on next-line therapy (PFS2) were assessed for L+P and S. PFS, ORR and DOR were assessed per independent review using RECIST v1.1. Nominal P-values are shown. Results: At a median follow-up (IQR) of 49.8 mos (41.4–53.1) for L+P and 49.4 mos (41.6–52.8) for S, 149 and 159 deaths had occurred, respectively. OS benefit with L+P vs S was maintained (HR, 95% CI; 0.79, 0.63–0.99). OS favored L+P vs S across MSKCC risk groups (HR, 95% CI; favorable [fav]: 0.89, 0.53–1.50; intermediate [int]: 0.81, 0.62–1.06; poor: 0.59, 0.31–1.12). PFS benefit of L+P vs S was maintained (HR, 95% CI; 0.47, 0.38–0.57). PFS favored L+P vs S across MSKCC risk groups (HR, 95% CI; fav: 0.46, 0.32–0.67; int: 0.51, 0.40–0.65; poor: 0.18, 0.08–0.42). ORR was greater with L+P (71.3%; complete response [CR], 18.3%) vs S (36.7%; CR, 4.8%) (relative risk, 95% CI; 1.94, 1.67–2.26). Less pts in the L+P arm (181/355, 51.0%) received subsequent anticancer therapies compared with the S arm (246/357, 68.9%); 56 (15.8%) and 195 (54.6%) received PD-1/PD-L1 checkpoint inhibitors, respectively. Analysis of OS adjusted for subsequent therapies will be presented. PFS2 was longer with L+P vs S (43.3 vs 25.9 mos; HR, 95% CI; 0.63, 0.51–0.77). Grade ≥3 treatment-related adverse events occurred in 74.1% and 60.3% pts in the L+P and S arms, respectively. Conclusions: L+P continues to demonstrate clinically meaningful benefit vs S in OS, PFS, ORR, and CR in the 1L treatment of pts with aRCC at 4-yr follow-up, thus supporting the robustness of the primary analysis data from CLEAR. Clinical trial information: NCT02811861 .[Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: There is currently no consensus on the role of upfront ASCT for patients with T cell Non-Hodgkin lymphomas (T-NHL), especially in patients who have achieved complete remission (CR1) following induction chemotherapy. To date, no randomized control trials (RCTs) exist and available data is conflicting, especially with regards to T-NHL subtypes that might benefit. A systematic review and meta-analysis of all comparative studies (randomized, non-randomized and observational) was hence performed to address this question. Methods: A comprehensive, systematic search (from 1/2000 to 2/2022) of MEDLINE/PubMed, EMBASE and Cochrane databases was performed. PRISMA and Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Studies were screened based on predefined inclusion/exclusion criteria, and were critically appraised for outcomes of interest [progression free survival (PFS) and overall survival (OS)]. Quality of studies was assessed using Newcastle-Ottawa Scale. Hazard ratios (HRs) and corresponding 95% Cis were calculated, and the meta-analysis was performed using the random-effects model. Test for heterogeneity was performed using I2 statistic. Results: Of 3297 unique records, 17 studies (prospective = 6, retrospective = 11) were included. Median follow up in these studies ranged from 22 to 94 mths. Ten studies compared upfront ASCT versus No ASCT in patients with complete remission (CR1), while in 7 patients achieving either PR1 (first partial remission) or CR1 were included[MS1]. Of these, 9 studies included only transplant eligible patients. The T-NHL subtypes included in the studies were also heterogenous, with nodal T-NHLs, in particular Angioimmunoblastic T-NHL (AITL) being amongst the most common subtypes. Results: from the meta-analysis showed that PFS in T-NHL patients who underwent ASCT benefited (HR 0.64, 95% CI: 0.46–0.89, I2 = 74%) compared to not undergoing ASCT; however similar benefit was not observed in OS (HR 0.67, 95% CI: 0.36–1.23, I2 = 89%). Sensitivity analyses including only studies with patients transplanted in CR1, and studies involving transplant eligible patients showed similar findings. In the studies that evaluated patients with the AITL subtype, ASCT showed a significant benefit in PFS and OS, compared to not undergoing ASCT (PFS = HR 0.19, 95% CI: 0.11–0.32, I2 20%; OS = HR 0.27, 95% CI: 0.09–0.81, I2 88 (Figure 1). Keyword: stem cell transplant No conflicts of interests pertinent to the abstract.

Time to treatment failure (TTF) and overall survival (OS) with palbociclib (PAL) plus endocrine therapy (ET) versus ET in HR+/HER2- advanced breast cancer (ABC) patients: A real-world multicenter study from China.

e13048 Background: Randomized controlled trials (RCTs) found that PAL plus ET had a considerable survival advantage in patients with HR+/HER2- ABC compared to ET. This real-world study aimed to complement the existing RCTs in addition to accounting for patient characteristics, adherence to treatment, and socioeconomic factors. Methods: Data of patients who had HR+HER2- ABC and received PAL plus ET (N=216) and ET (N=215) from September 2007 to May 2020 were retrospectively retrieved from the electronic medical record system of seven cancer centers across China. Stabilized inverse probability of treatment weighting (SIPTW) was applied to strictly balance the variables between the two cohorts. Results: A total of 400 patients were eligible for the study analysis. PAL plus ET was administered to 204 (51%) patients, and 196 (49%) patients received ET only. At the end of the observation, treatment failure occurred in 162 (79%) patients and 183 (93%) patients in both cohorts, due to disease progression (93.2% vs. 96.8%), financial inability (4.9% vs. 0%), intolerable adverse reactions (1.9% vs. 0.5%), and unknown reasons (0% vs. 2.7%). Most patients were postmenopausal (71.8%) and had visceral metastasis (65.2%). De-novo metastatic disease was seen in 13.0% of patients, and 45.2% of patients received first-line ET. More than half of the patients (57.8%) received aromatase inhibitors, and 38.5% received estrogen receptor degrader fulvestrant. With a median follow-up period of 39.5 and 40.5 months, the median TTF in PAL plus ET vs. ET was 11.8 vs. 9.47 months (HR=0.69, 95% CI: 0.56-0.86, p=0.00057), and OS analysis showed a median OS not reached (NR) vs. 40.7 months (HR=0.84, 95% CI: 0.62-1.13, p=0.25). Upon SIPTW, the standardized differences (-0.117 to 0.096) showed a good balance between the cohorts. Weighted median TTF was significantly longer in the PAL plus ET group than the ET group (11.8 vs. 7.07 months, HR=0.63, 95% CI: 0.49-0.80, p=0.000139). However, the results of weighted median OS were not statistically significant (NR vs. 38 months, HR=0.80, 95% CI: 0.53-1.21, p=0.29). In the balanced subgroup analysis, TTF showed a similar trend to that in the overall population, and in patients with de-novo metastatic disease and non-central nervous system (CNS) metastasis, OS was significantly longer in the PAL plus ET group than ET (HR=0.256, 95% CI: 0.112-0.586, p for interaction=0.013; HR=0.657, 95% CI: 0.443-0.973, p for interaction=0.013, respectively). Conclusions: Comparatively, PAL plus ET had significantly longer TTF than ET, supporting the use of PAL plus ET in HR+/HER2– ABC patients in real-world settings. In patients with de-novo metastatic disease and non-CNS metastasis, PAL plus ET showed significant OS benefit compared to ET, however, follow-up time needs to be increased in further studies.

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Final overall survival and biomarker analyses of CHOICE-01: A double-blind randomized phase 3 study of toripalimab versus placebo in combination chemotherapy for advanced NSCLC without EGFR/ALK mutations.

9003 Background: Toripalimab in combination with chemotherapy showed significant improvement over chemotherapy alone in progression-free survival (PFS) and overall survival (OS) as first-line treatment of advanced NSCLC at the final PFS analysis of the CHOICE-01 study (NCT03856411). Here we report the final OS analysis. Methods: Patients (n=465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n=309) or placebo (n=156) in combination with chemotherapy for 4-6 cycles, followed by maintenance toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Patients from the placebo arm were actively crossed-over to receive toripalimab upon disease progression. The primary endpoint was PFS. The secondary endpoints included OS and safety. Results: By the cutoff date of August 31, 2022, when 283 events triggered the final OS analysis, the median survival follow up was 19.4 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR=0.73 (95% CI: 0.57-0.93), two-sided p=0.0108, median OS 23.8 vs 17.0 months. A consistent effect on OS, favoring the toripalimab arm, was observed all PD-L1 expression subgroups. The OS benefit is greater in non-squamous NSCLC, HR=0.50 (95% CI: 0.36-0.70), median OS 27.8 vs 15.9 months, whereas no significant difference was found in the squamous subgroup (mOS 19.6 vs 18.1 months) despite a significant PFS improvement. The squamous subgroup had a high 70% crossover rate. No new safety signal was identified since the interim report. The incidence of Grade ≥3 adverse events (AEs) (78.9% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%), fatal AEs (5.5% vs 2.6%), and immune-related (irAEs) (50.6% vs. 21.2%) were more frequent in the toripalimab arm. Whole exome sequencing results indicated patients with mutations in the FAK-PI3K-Akt pathway achieved significantly better OS from the toripalimab arm. Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided significant OS benefit than chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411 .

Efficacy and safety of first-line treatments for patients with advanced hepatocellular carcinoma: A systematic review and network meta-analysis.

4094 Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.

Progression-free survival as a surrogate endpoint of overall survival in advanced biliary tract cancer: A meta-analysis of randomized trials and individual-patient level correlation.

4101 Background: Biliary tract cancer (BTC) is a heterogeneous group of diseases commonly diagnosed at advanced stages. Overall survival (OS) is the gold-standard primary endpoint in randomized controlled trials (RCT). However, the increasing use of subsequent lines of therapies and cross-over designs may confound the treatment effect. We therefore explored the use of progression free survival (PFS) as a surrogate endpoint of OS both at the trial-level and at the patient-level. Methods: For the trial-level correlation, we conducted a systematic review of RCTs in advanced BTC following the PRISMA guidelines. We searched PubMed, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from database inception to June 2022 and identified all randomized phase II/III trials testing systemic therapies for advanced BTC. We used a weighted linear regression to measure the correlation of log-transformed hazard ratios (HR) of OS and PFS based on trial size and calculated the surrogate threshold effect (STE). We used the IQWiG framework to define the strength of evidence. For the individual-level analysis, we included patients with advanced BTC treated with first and second line chemotherapy in the real-world RETUD registry. We estimated the correlation via the iterative multiple imputation method. Results: From a total of 1992 studies, we identified 32 RCTs including 70 treatment arms and 5140 patients that fulfilled the inclusion criteria. Twenty-three trials were performed in the first line setting and most were phase II RCTs (N = 23). We found a moderate correlation between OS and PFS ( R= 0.79, 95% CI 0.61-0.89). The slope of the regression line was 0.62±0.08, indicating that a 10% risk reduction in PFS will result in a 6.2%±0.8% improvement in OS. The STE was 0.69, suggesting that in a hypothetical trial of 400 patients, a PFS HR of 0.69 will likely result in a significant improvement on OS. Regarding the individual-level correlation, a total of 593 patients with advanced BTC were included. The median age of patients was 68y (IQR 59-74), most were males (54%) and received platinum-based chemotherapy (73.1%). In the first line setting, the median OS was 9.7 months (95% CI 8.7-10.5) and median PFS was 5 months (95% CI 4.5-5.5). We observed a strong correlation between PFS and OS ( r= 0.84, 95% CI 0.81-0.86). In the second line setting (N = 259), a similar correlation was observed to the first-line setting ( r= 0.76, 95% CI 0.72-0.8). Conclusions: At the trial-level, in this analysis treatment effects on PFS were moderately correlated with OS. A HR < 0.69 in PFS suggested that it would likely lead to a significant OS benefit in a hypothetical trial including 400 patients. At the individual-level, PFS and OS were strongly correlated in a real-world cohort. Future validation in patients treated in the context of randomized trials is warranted.

Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC).

1003 Background: Treatment of HR+/HER2– mBC includes sequential endocrine therapy (ET) combined with targeted agents followed by sequential single-agent chemotherapy (CT), which is associated with poor outcomes and quality of life. SG is a Trop-2–directed antibody-drug conjugate approved in multiple countries for pts with metastatic triple-negative breast cancer who received ≥1 prior systemic therapy and in the US for pts with pretreated HR+/HER2- mBC. In the phase 3 TROPiCS-02 study, SG demonstrated a statistically significant OS benefit versus treatment of physician’s choice (TPC) in pts with pretreated, ET-resistant HR+/HER2– mBC at the 2nd planned interim OS analysis with 390 events (median, 14.4 vs 11.2 mo; HR, 0.79 [95% CI, 0.65-0.96]; P=0.02; Rugo HS, et al. ESMO 2022. LBA76); this is considered the final analysis per the protocol. Here, we report the results of an exploratory analysis of OS from TROPiCS-02 with a longer median follow-up (12.75 mo). Methods: Eligible pts withHR+/HER2– mBC who received prior taxane, ET, CDK4/6 inhibitor, and 2-4 prior lines of CT were randomly assigned 1:1 to receive SG (10 mg/kg IV d1 and 8, every 21 d) or TPC until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival by blinded independent central review per RECIST v1.1. Key secondary endpoints included OS and safety. In an exploratory analysis, we evaluated OS by HER2 immunohistochemistry (IHC). Results: In total, 543 pts (median prior CT for mBC, 3; visceral metastases, 95%) were randomized to receive SG (n=272) or TPC (n=271). At data cutoff (Dec 1, 2022), 437 OS events had occurred (median follow-up, 12.75 mo), with 47 (8.7%) new deaths in the SG versus TPC groups (22 [8.1%] vs 25 [9.2%]) since the 2nd planned interim analysis. With this extended follow-up, SG continues to demonstrate improved OS versus TPC (median, 14.5 vs 11.2 mo; HR, 0.79 [95% CI, 0.65-0.95]; nominal P=0.01). The OS rates (95% CI) for SG versus TPC were 60.9% (54.8-66.4) and 47.1% (41.0-53.0) at 12 months, 39.2% (33.4-45.0) and 31.7% (26.2-37.4) at 18 months, and 25.6% (20.4-31.1) and 21.1% (16.3-26.3) at 24 months. Overall, 92% of pts were evaluable for HER2 status by IHC (HER2 IHC0, n=217; HER2-low, n=283). SG demonstrated improved OS versus TPC in the HER2 IHC0 (median, 13.6 vs 10.8 mo; HR, 0.86 [95% CI, 0.63-1.13]) and HER2-low (median, 15.4 vs 11.5 mo, HR, 0.74 [95% CI, 0.57-0.97) groups. Updated safety will be reported at the time of presentation. Conclusions: The final OS analysis of the TROPiCS-02 study confirms the clinically meaningful OS benefit of SG over single-agent CT in pts with pretreated, endocrine-resistant HR+/HER2–mBC. This improvement was independent of HER2-low status. This analysis reinforces SG as an effective and safe treatment for this pt population with limited treatment options. Clinical trial information: NCT03901339 .

ORACLE-RIPA study: A phase II, randomized, open-label, parallel-group study comparing the immune modulation effect of neoadjuvant ribociclib, palbociclib, and abemaciclib in early ER+/HER2- breast cancer.

TPS632 Background: CDK4/6 inhibitors (CDK4/6i), ribociclib, palbociclib, and abemaciclib, provide similar progression-free survival (PFS) benefits when combined with endocrine therapy in ER+/HER2- metastatic breast cancer (MBC) patients. However, not all CDK4/6i have demonstrated overall-survival (OS) benefits in their respective phase III trials. Both, ribociclib and abemaciclib, have shown significant OS benefits in ER+/HER2- MBC patients, but palbociclib has not. Because of similar benefits of the 3 CDK4/6i on PFS, the OS benefit is likely not a result of differences in their synergistic efficacy of a CDK4/6i with endocrine therapy. CDK4 inhibition on cancer cells can also result in upregulation of MHC-I and MHC-II expression on cell surface and Rb-dependent interferon-gamma secretion. CDK6 inhibition might inhibit T cell and NK cell proliferation causing a negative effect on the tumor microenvironment. CDK6 inhibition can also reduce regulatory T cell numbers and increase cytokine production to enhance cytotoxic T cell function. Thus, we hypothesize that the differential impact of the 3 CDK4/6i on OS might be resulting from different immunomodulation effects. To investigate the functional alterations of the CDK4/6i on the BC microenvironment, the neoadjuvant treatment setting is best to compare the immune modulation effects of CDK4/6i from pre-treatment and post-treatment tumor tissues. Methods: This phase II multicenter, randomized, open-label, parallel-group study evaluates the immunomodulation effects of the 3 different CDK4/6i (ribociclib, palbociclib, or abemaciclib) combined with letrozole in neoadjuvant early ER+/HER2- breast cancer patients. A total of 20 patients will be enrolled into each treatment arm. The major inclusion criteria are female patients aged ≥ 20 years old, having a histologically and/or cytologically confirmed diagnosis of ER+ ( > 10%) and/or PR+, HER2 negative (IHC 0+/1+, or IHC 2+ plus FISH negative) breast cancer, stage II/III, and adequate organ function. The treatment will12 weeks of letrozole plus a CDK4/6i. Premenopausal patients will receive GnRH agonist. Breast tumor biopsy, blood and stool samples will be collected prospectively at the time prior to treatment initiation, at 2 weeks after treatment, and at surgery. A description summary will be utilized to compare the results between the 3 CDK4/6i. The trial results will address questions about differences or similarities of the 3 CDK4/6i within the same study. The study is currently enrolling at 3 medical centers s in Taiwan. Clinical trial information: Pending formal number assignment .

Hepatocellular Carcinoma: A Review

Hepatocellular Carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. Several risk factors responsible for development of HCC are liver and biliary Cirrhosis, Alcohol consumption, Hepatitis B and C infection, exposure to carcinogenic substance like Aflatoxin and Arsenic, comorbid condition like Obesity and Diabetes etc. In this review we discus about risk factors, screening methods and stages of HCC. Multiple treatment availability such as Radiation therapy, Chemotherapy and Surgical procedures along with newer modalities like Targeted Drug Delivery System, use of nano technology, newer Immunomodulators and Radiofrequency Ablation. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival.

Efficacy of PD-1/PD-L1 inhibitors in advanced gastroesophageal cancer based on characteristics: a meta-analysis.

Objective: Evaluate the potency of anti-PD-1/PD-L1 antibodies in advanced gastroesophageal cancer patients with different clinical features. Methods: Randomized, controlled trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy in individuals with gastroesophageal cancer were retrieved. Results: 15trials involving 9194 individuals were included. PD-1/PD-L1 inhibitors significantly improved overall survival (OS) but not progression-free survival. Significantly improved OS was observed in PD-L1 combined positive score ≥1, primary esophageal cancer, primary gastric cancer and Asian patients. Subgroup analysis revealed significant OS benefit achieved for esophageal squamous cell carcinoma, but not for esophageal adenocarcinoma. Conclusion: PD-1/PD-L1 inhibitors improved OS in advanced gastroesophageal carcinoma, especially in patients with esophageal cancer. Race, primary tumor sites and PD-L1 combined positive score can be used to predict the potency of immune checkpoint inhibitors.

RE-MIND2: comparative effectiveness of tafasitamab plus lenalidomide versus polatuzumab vedotin/bendamustine/rituximab (pola-BR), CAR-T therapies, and lenalidomide/rituximab (R2) based on real-world data in patients with relapsed/refractory diffuse large B-cell lymphoma

RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis.Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival.From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892).Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL.Clinical trial registrationNCT04697160 (January 6, 2021)

BITH, a blood-based metric of intratumor heterogeneity, is associated with clinical response to immune checkpoint blockade in non-small cell lung cancer

Intratumor heterogeneity (ITH) has been associated with poor prognosis in advanced non-small cell cancer (NSCLC) patients receiving immune checkpoint blockade (ICB) therapies. However, there is currently no evidence supporting an ITH metric as a predictor of clinical benefit from ICB. The unique advantages of blood make it a promising material for ITH estimation and relevant applications. This study aims to develop and validate a blood-based ITH index for predicting ICB response. NSCLC patients from the OAK and POPLAR clinical trials were used as the training cohorts for algorithm development. Survival analyses with overall survival (OS) and progression-free survival (PFS) as endpoints were performed to assess clinical response. The predictive value of bITH was subsequently validated with an independent cohort of 42 NSCLC patients treated with PD-1 blockade. bITH was significantly associated with the differential OS and PFS elicited by atezolizumab vs. docetaxel in both univariable and multivariable analyses in the OAK patients, suggesting bITH as an independent predictor for response to ICB. Moreover, compared with blood tumor mutation burden (bTMB), bITH enabled greater OS segregation and comparable PFS segregation, and obtained a predictive role regardless of bTMB status. Moreover, the association between bITH and PFS was validated with an independent cohort. Patients with low blood-based ITH metric manifest significant OS and PFS benefit from immunotherapy versus chemotherapy. Future research is awaited to corroborate our findings and to enrich the clinical utility of ITH. This study was supported by the National Natural Science Foundation of China (Nos. 81972718 and 81572321), the Natural Scientific Foundation of Zhejiang Province, China (No. LY19H160007), the Science and Technology Program for Health and Medicine in Zhejiang Province, China (No. 2021KY541), the Scientific Research Project, Science and Technology Department of Sichuan Province (No. 21YYJC1616), the Scientific Research Project, Sichuan Medical Association (No. S20002), Wu Jieping Medical Foundation (No. 320.6750), and 2018 Entrepreneurial Leading Talent of Guangzhou Huangpu District and Guangzhou Development District (No. 2022-L023).

Low versus high dose of postoperative radiotherapy for locally advanced esophageal squamous cell carcinoma: a propensity score‐matched analysis

AbstractObjectiveThis study aimed to investigate the effect of different postoperative radiotherapy doses on the prognosis of patients with esophageal squamous cell carcinoma (ESCC).MethodsA total of 199 patients (aged 18–75 years) with locally advanced ESCC who underwent esophagectomy and postoperative radiotherapy/chemoradiotherapy at the Fujian Cancer Hospital between July 2008 and January 2018 were included. Based on the postoperative radiotherapy dose, the patients were divided into a low‐dose group (50–50.4 Gy; median dose 50 Gy) and a high‐dose group (>50.4 Gy; median dose 60 Gy). Neoadjuvant and adjuvant chemotherapy regimens included PF (fluorouracil and cisplatin) and TP (paclitaxel and cisplatin) regimens. Patients were followed‐up every 3 months in the first 2 years after surgery, every 6 months for the next 3 years, and then subsequently once a year. The primary endpoints were overall survival (OS) and progression‐free survival (PFS) rates. The propensity‐score matching (PSM) method was applied to identify a 1:1, well‐balanced matched cohort with 33 patients in each group for survival comparison.ResultsAmong the 199 patients enrolled in this study, 144 and 55 were in the low‐dose and high‐dose groups, respectively. Univariate and multivariate analyses showed that pathological N classification, vascular tumor emboli, and postoperative radiotherapy dose were independent prognostic factors for both OS and PFS, all p < 0.05. Before PSM, the OS and the PFS of the low‐dose group were significantly longer than those of the high‐dose group, both p < 0.05. After PSM, better OS and PFS rates were observed in the low‐dose group, both p < 0.05. The results showed that patients with pathological stages N0–2 or N3, negative surgical margins, and no vascular tumor emboli could obtain a significant benefit in both OS and PFS after treatment with a low dose of postoperative radiotherapy (50–50.4 Gy). In the subgroup with positive surgical margins, treatment with a low dose of postoperative radiotherapy offered a non‐significant survival benefit compared to treatment with a high dose of postoperative radiotherapy.ConclusionsOur study revealed that for patients with ESCC, the low‐dose group (50–50.4 Gy) had a significantly higher OS and PFS than the high‐dose group (>50.4 Gy). It was suggested that 50–50.4 Gy might be the recommended postoperative radiotherapy dose for ESCC patients.

Identifying optimal first-line immune checkpoint inhibitors based regiments for advanced non-small cell lung cancer without oncogenic driver mutations: A systematic review and network meta-analysis.

Immune checkpoint inhibitors (ICIs) have changed the treatment pattern of advanced and metastatic NSCLC. A series of ICI based therapies have emerged in the first-line treatment field, but the comparative efficacy was unclear. We searched multiple databases and abstracts of major conference proceedings up to Apri1, 2022 for phase III randomised trials of advanced driver-gene wild type NSCLC patients receiving first-line therapy. Outcomes analyzed included progression free survival (PFS), overall survival (OS), and et al. Thirty-two double-blind RCTs were included, involving 18,656 patients assigned to 22 ICI-based first-line regimens. A series of ICI regiments (including ICI plus chemotherapy), ICI monotherapy, doublet ICIs, doublet ICIs plus chemotherapy) emerged, and showed significant PFS and OS benefit than chemotherapy and chemotherapy + bevacizumab (BEV) for advanced wild-type NSCLC. In comprehensive terms of PFS, chemoimmunotherapy (CIT) were significantly more effective than ICI monotherapy and doublet ICIs. In terms of OS for patients with non-squamous NSCLC, pembrolizumab containing CIT was associated with a median rank of the best regimens, and followed by Atezolizumab+BEV based CIT; while for OS in patients with squamous NSCLC, Cemiplimab and sintilimab based CIT were the most effective regimens. For more than 2 years follow-up, the atezolizumab, pembrolizumab, nivolumab and durvalumab containing ICI therapy all provide a durable long-term OS benefit over chemotherapy and BEV + chemotherapy. The findings of the present NMA represent the most comprehensive evidence, which might suggest or provide basis for first-line ICI therapy decision for advanced NSCLC patients without oncogenic driver mutations.

Abstract CT078: First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial

Abstract Background: The phase III ORIENT-16 trial evaluated sin (a PD-1 inhibitor) versus placebo plus chemo as first-line (1L) treatment in pts with advanced G/GEJ adenocarcinoma. Sin+chemo previously showed a significant improvement in OS vs chemo in pts with PD-L1 combined positive score (CPS) ≥5 (HR 0.660; 95% CI 0.505-0.864; P=0.0023) and in all pts (HR 0.766; 95% CI 0.626-0.936; P=0.0090), with a median follow-up of 18.8 months (m) at interim analysis (Xu, et al. Ann Oncol 2021). Here we report the results from the final analysis (NCT03745170). Methods: This double-blind, phase III trial enrolled 650 pts ≥18 years of age with untreated, unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma, regardless of PD-L1 expression. Pts were randomized 1:1 to receive sin (3 mg/kg in pts weighing <60 kg or 200 mg in pts weighing ≥60 kg, IV Q3W) or placebo plus chemo (oxaliplatin 130 mg/m2 IV Q3W for up to 6 cycles, capecitabine 1000 mg/m2 PO Bid d1-14 Q3W) for 24 months. The primary endpoints were OS in pts with CPS ≥5 and all randomized pts. The data cutoff date for the final analysis was Sep 2, 2022. Results: With a median follow-up of 33.9 m, sin+chemo continued to show OS benefit over chemo in all pts (15.2 vs 12.3 m; HR 0.681 [95% CI: 0.571, 0.812]; P<0.0001); estimated OS rates at 24 and 36 m for sin+chemo vs chemo were 37.6% vs 20.6% and 26.0% vs 10.7%, respectively. OS benefits with sin+chemo vs chemo across subgroups were generally consistent with the previous report. The updated PFS was superior with sin+chemo vs chemo (HR 0.638, 95% CI 0.530-0.768; P<0.0001). The updated confirmed ORR per RECIST v1.1 was 58.2% vs 48.8% in all pts with measurable disease at baseline, with a median DoR of 9.9 vs 7.0 m, respectively; 47.8% of responders in sin+chemo group and 25.9% of responders in chemo group had DoR ≥12 m. In pts with CPS ≥5, significant OS benefit (median OS 19.2 vs 12.9 m; HR 0.587 [95% CI: 0.467, 0.738]; P<0.0001) and superior PFS (HR 0.621, 95% CI 0.490-0.787; P<0.0001) with sin+chemo over chemo remained. A delayed numerical OS improvement was observed for subgroup pts with CPS <5. No new or unexpected safety signals were identified. Conclusion: The previously reported significant OS benefit with sin+chemo vs chemo was more evident in CPS ≥5 pts and in all pts with 15 m of additional follow-up, further confirming sin+chemo as a standard of care for 1L treatment of G/GEJ adenocarcinoma. Citation Format: Jianming Xu, Haiping Jiang, Yueyin Pan, Kangsheng Gu, Shundong Cang, Lei Han, Yongqian Shu, Jiayi Li, Junhui Zhao, Hongming Pan, Suxia Luo, Yanru Qin, Qunyi Guo, Yuxian Bai, Yang Ling, Yingmei Guo, Yuling Chen, Yan Wang, Hui Zhou. First-line treatment with sintilimab (sin) vs placebo in combination with chemotherapy (chemo) in patients (pts) with unresectable gastric or gastroesophageal junction (G/GEJ) cancer: Final overall survival (OS) results from the randomized, phase III ORIENT-16 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT078.